Perioperative and palliative systemic treatments for biliary tract cancer

Due to the fact biliary tract cancer (BTC) is often diagnosed at an advanced stage, thus, not eligible for resection, and due to the aggressive tumor biology, it is considered as one of the cancer types with the worst prognosis. Advances in diagnosis, surgical techniques, and molecular characterization have led to an improvement of the prognosis of BTC patients, recently. Although neoadjuvant therapy is expected to improve surgical outcomes by reducing tumor size, its routine is not well established. The application of neoadjuvant therapy in locally advanced disease may be indicated, the routine use of systemic therapy prior to surgery for cholangiocarcinoma patients with an upfront resectable disease is less well established, but discussed and performed in selected cases. In advanced disease, only combination chemotherapy regimens have been demonstrated to achieve disease control in untreated patients. Molecular profiling of the tumor has demonstrated that many BTC might bear actionable targets, which might be addressed by biological treatments, thus improving the prognosis of the patients. Furthermore, the addition of the immunotherapy to standard chemotherapy might improve the prognosis in a subset of patients. This review seeks to give a comprehensive overview about the role of neoadjuvant as well as palliative systemic treatment approaches and an outlook about novel systemic treatment concept in BTC.


Introduction
Biliary tract cancer (BTC) represents the second most frequent type of hepatobiliary malignancies and is an aggressive and fatal cancer originating from the epithelium lining of the bile ducts and gall bladder.2][3][4] However, its incidence is clearly increasing.3][4] Each of these subtypes has a distinct molecular signature highlighting the high spatial heterogeneity in this disease group. 8,9][12] However, due to the vague symptoms of the disease, it is often diagnosed in an advanced stage not amenable to surgical resection. 13For a long time, therapeutic options for metastatic BTC were limited with a dismal 5-year survival rate of only 2%. 14cently, molecular profiling and the development of new drugs with innovative mode of actions, such as immune checkpoint inhibitors and small molecular agents as targeted therapies have enriched the therapeutic armamentarium and -at the same time -increased the complexity of BTC management. 15 this review, we give a detailed overview about curative treatment strategies of BTC and discuss the palliative therapies, including the immunotherapy and the molecular-guided targeted drugs.

Rationale for neoadjuvant therapy
The rationale for the use of neoadjuvant treatment in cholangiocarcinoma is based on several concepts: First, it is postulated that systemic therapy prior to surgery may achieve an eradication of potential micrometastatic disease and consequently a decrease of early recurrence.Additionally, it may help identify patients, who are more prone for developing a progressive disease, which renders them unsuitable for a surgical approach.Another argument in favor of neoadjuvant treatment derives from the observation that it may downsize the primary tumor and thus improve margin-negative resection rate.Furthermore, as patients sometimes experience a delay of adjuvant chemotherapy initiation due to postoperative complications or poor performance status after major liver surgery, preoperative treatment may be considered as an alternative way to increase the receipt of systemic therapy.However, despite these theoretical advantages, it still remains unclear whether neoadjuvant therapy in resectable cholangiocarcinoma is actually associated with a more favorable outcome compared to those, who receive upfront surgical resection.To date, there are no conclusive results from large prospective studies available as of yet, although retrospective analyses have shown a trend toward a survival benefit in patients undergoing neoadjuvant therapy followed by surgery.With the advent of novel treatment strategies for cholangiocarcinoma in recent years, particularly in the field of precision medicine and immunotherapy, several prospective clinical trials are in progress with the aim of investigating the use of neoadjuvant chemotherapy combined with other treatment regimens in (borderline) resectable cholangiocarcinoma.In the following paragraphs, we will outline and discuss available data on the use of neoadjuvant therapy in extrahepatic and intrahepatic cholangiocarcinoma, as well as summarize selected prospective clinical trials that are currently ongoing.

Extrahepatic cholangiocarcinoma
For patients with phCCA and dCCA, radical surgical resection remains the only potentially curative treatment strategy.In phCCA, surgical therapy is based on extended hepatectomy and bile duct resection including lymphadenectomy and hepaticojejunostomy, whereas patients with dCCA usually undergo a Whipple procedure with pancreaticoduodenectomy. Due to the fact that most patients with an extrahepatic cholangiocarcinoma are diagnosed at an advanced stage (i.e.portal vein invasion, infiltration of the biliary ducts, hepatic artery invasion), the majority of available retrospective analyses on neoadjuvant therapy are conducted in this subtype (Table 1).In 1997, McMasters et al. performed a prospective study with nine participants (four dCCA and five phCCA, all unresectable), who received preoperative chemoradiation with 5-FU and external beam radiotherapy (EBRT) prior to hepatic resection.Interestingly, three patients had a pathologic complete response (pCR), whereas R0 resection was achieved in all nine eCCA patients.In the phCCA cohort, none of the patients developed a recurrence.However, in all four dCCA patients, recurrent disease was observed shortly after surgery despite R0 resection.This study has been the first one to report an encouraging safety and efficacy of neoadjuvant chemoradiation in patients with eCCA. 16In recent years, several small size retrospective studies followed.Among them, a study led by Nelson et al. investigated the efficacy of preoperative 5-FU and EBRT ± brachytherapy in 12 unresectable eCCA patients.The authors observed a R0 resection rate of 91.7% with three patients having a pCR and concluded that these results further strengthened the hypothesis that neoadjuvant treatment may enhance the probability of converting unresectable eCCA to a resectable disease. 17Likewise, in 2017 Jung et al. also conducted a retrospective analysis, in which 12 patients with unresectable phCCA were treated with 5-FU or Gemcitabine and EBRT, Table 1.The results from this retrospective study revealed an improvement of 3-year DFS (78% versus 57%) and 3-year overall survival (OS) (85% versus 69%) in the neoadjuvant cohort.Nevertheless, large sized randomized clinical trials are warranted to validate these findings and further explore the efficacy of this treatment strategy.

Intrahepatic cholangiocarcinoma
With regards to iCCA, current evidence is sourced from a limited number of retrospective cases series evaluating the benefits of neoadjuvant treatment mostly in unresectable iCCA patients (Table 1).Similar to other subtypes of CCA, surgery remains the mainstay of curative therapy for iCCA.So far, combined treatment modalities including chemotherapy, radiation, local liverdirected therapies have provided intriguing results in the preoperative setting and form the basis for further in-depth analyses.Two of these studies were conducted by Kato et al. with the primary aim of investigating the efficacy of Gemcitabinebased chemotherapy.In the Gemcitabine monotherapy cohort with 22 iCCA patients, 37% of patients were successfully converted to a resectable disease.In the resected group, a mOS of 19.3 months was reported. 21In contrast to that, 39 iCCA patients received the combination of Gemcitabine and Cisplatin preoperatively, resulting in a conversion rate to surgery of 26% and mOS of 17.9 months. 22reover, Omichi et al. observed in 43 patients with borderline resectable or unresectable iCCA a 100% conversion rate to resection and a 5-year RFS of 48% following neoadjuvant treatment with Gemcitabine-based chemotherapy. 23teresting results were recently also published by a French group led by Le Roy et al., where 74 initially unresectable iCCA patients received Gemcitabine and Oxaliplatin in the neoadjuvant setting, of which 53% underwent surgery and 31% had a R0 resection.Of note, mOS of patients with unresectable disease treated with a median length of six cycles of systemic therapy followed by surgery was 24.1 months, which is comparable to the mOS of the resectable patient cohort treated with surgery alone (25.7 months).Consequently, similar outcomes were observed in patients with unresectable iCCA undergoing neoadjuvant chemotherapy followed by surgery and iCCA patients with a resectable tumor. 24

Ongoing prospective neoadjuvant trials in cholangiocarcinoma
To date, there are multiple clinical trials ongoing investigating the feasibility and efficacy of neoadjuvant systemic therapy in resectable, as well as in locally advanced cholangiocarcinoma (Table 2).
An emphasis has been placed on patients with upfront resectable iCCA.The triple combination of chemotherapy with Cisplatin + Gemcitabine + nab-Paclitaxel is currently being evaluated within the phase II study NEOGAP (NCT03579771), where the primary endpoints are the completion of all preoperative and operative therapy and the incidence of adverse events.A preliminary report has been presented at the 2022 annual meeting of the American Society of Clinical Oncology: Of 30 patients in total, 77% completed all preoperative chemotherapy and received curative-intent resection, with 33% developing grade 3 treatmentrelated adverse events, most commonly neutropenia or diarrhea.As for the response rate, the disease control rate was 90% with 23% partial response, 67% stable disease and 10% progressive disease. 25NCT03603834 is another neoadjuvant chemotherapy study, where (potentially) resectable CCA patients receive mFOLFOXIRI preoperatively.The primary outcome of this trial is the rate of overall response evaluated by MR or CT within the time frame of up to 15 weeks. 26In contrast, NCT04669496 is a phase II-III clinical trial evaluating the combined use of the PD-1 antibody Toripalimab + GEMOX + Lenvatinib versus observation in resectable iCCA patients with high-risk recurrence factor. 27After surgical resection, adjuvant chemotherapy consisting of Capecitabine monotherapy will be administered to all patients.The primary outcome is event-free survival within 24 months.Furthermore, a phase

Neoadjuvant therapy and liver transplantation in cholangiocarcinoma
The current status of liver transplantation for the treatment of cholangiocarcinoma is based on the concept that liver transplantation might offer advantages over liver resection, with an improved probability of achieving negative oncologic margins, whereas eliminating intrahepatic micrometastases and resolving any preexisting liver disease at the same time. 33The most established protocol to date has been published by the Mayo Clinic Group, employing neoadjuvant chemoradiation followed by liver transplantation as a definitive therapy for patients with perihilar CCA. 34Essentially, early stage perihilar CCA patients with <3 cm lesions on imaging without metastasis or lymph node involvement, who are technically unresectable, will undergo endoscopic ultrasound and fine needle aspiration of regional lymph nodes.Those with negative lymph nodes will receive chemoradiotherapy for 5 weeks.External beam radiation therapy, which is accompanied by 5-fluorouracil as a radiation-sensitizing agent, and intraductal radiation therapy will be applied sequentially, followed by oral capecitabine treatment until the patient undergoes liver transplantation.Subsequently, laparoscopic or open abdominal exploration will be performed to exclude metastasis and examine regional lymph nodes prior to liver transplantation.Posttransplantation management includes standard immunosuppressive treatment but no adjuvant systemic therapy.The cumulative dropout rate from the 'Mayo Protocol' reaches 46% by 12 months.OS at 5 years is 68% ± 3% and at 10 years is 60% ± 4%.The authors concluded that the majority of deaths following liver transplantation are due to recurrent disease. 34 contrast, the current data situation regarding the use of liver transplantation in intrahepatic CCA is not clear and requires further in-depth exploration.Most literature on liver transplantation in iCCA focused on incidentally found tumors on explant livers or in patients who were transplanted for presumed HCC, which does not typically undergo neoadjuvant systemic therapy prior to transplant but rather only locoregional therapy. 35Consequently, substantial evidence is lacking to support protocols that combine neoadjuvant treatment with liver transplantation for iCCA.In fact, studies which include neoadjuvant therapy prior to liver transplantation are confined to small case series only.For instance, Lunsford et al. assessed 12 patients with non-metastatic unresectable iCCA >2 cm in size, who underwent neoadjuvant gemcitabine and platinumbased chemotherapy for 6 months.Six patients (50%) showed either stable disease or regression and proceeded to liver transplantation.The 5-year OS was reported with 83.3%. 36urthermore, Wong et al. performed a similar study with the addition of transarterial chemoembolization and pre-transplant operative staging.From the 18 patients, who started the neoadjuvant therapies, only 5 (27.8%) patients proceeded to liver transplantation.Follow-up at 1 year demonstrated an OS of 80%, whereas recurrence developed in two patients. 37l in all, patients with response to neoadjuvant therapy have better outcomes after liver transplantation compared to those without response to neoadjuvant therapy.Although more evidence is needed, there is an increasing opinion in favor of extending the indication of liver transplantation for unresectable iCCA.Based on the consensus statement from the European Network for the Study of Cholangiocarcinoma in 2020, liver transplantation should be considered, particularly in iCCA patients with very early-stage unresectable tumors (⩽2 cm) and concomitant cirrhosis. 38 the neoadjuvant setting, it is of utmost importance to preserve liver function in cirrhotic patients, while achieving optimal anti-tumor effect of the systemic therapy.Of note, in iCCA patients with underlying cirrhosis, liver transplantation may be regarded as a potential treatment strategy. 38

Adjuvant therapy for cholangiocarcinoma
In terms of adjuvant treatment strategy for BTC, six randomized phase II/III trials investigating the efficacy of adjuvant chemotherapy are currently available.Single-agent capecitabine was established as the standard treatment regimen in the adjuvant setting for BTC based on the results from the BILCAP trial. 39Although its primary outcome was not achieved in the intention-totreat population, it did demonstrate a statistically significant improvement in OS in the per-protocol analysis.Another limitation of this trial was the relatively long enrollment time from March 2006 to December 2014 to include 447 patients.
In contrast, ESPAC-3 was a phase III trial conducted to assess the efficacy of adjuvant chemotherapy using 5-fluorouracil and folinic acid or gemcitabine monotherapy versus surgery alone in patients with extrahepatic cholangiocarcinoma and ampullary carcinoma.Significant superiority of adjuvant chemotherapy over surgery alone was not achieved based on the intention-to-treat analysis. 40Similarly, gemcitabine-based chemotherapy -either gemcitabine alone in the BCAT study or gemcitabine in combination with oxaliplatin in the PRODIGE-12 -failed to show significant activity in the adjuvant setting. 10,41Of note, the randomized phase II STAMP trial, which was currently published by Jeong and Yoo explored the efficacy and feasibility of adjuvant gemcitabine combined with cisplatin (experimental arm) over capecitabine (control arm) in a specific subset of patients with BTC. 42Only patients diagnosed with extrahepatic cholangiocarcinoma (both hilar and distal cholangiocarcinoma), who had undergone curative surgery with R0 or R1 resection and who had a positive lymph node status in the surgical specimen were included in the STAMP trial.Despite the fact that the study failed to demonstrate an improvement in outcome in the gemcitabine/cisplatin cohort, the study design was positively highlighted due to its subgroup-specific nature, since the authors decided to focus on one specific subgroup of patients rather than recruiting patients with all types of biliary tract tumors.Finally, it is worth mentioning that the randomized phase III ASCOT study is the only recent positive adjuvant clinical trial. 43Single-agent fluoropyrimidinebased therapy with S1 demonstrated significant efficacy and improvement in survival in Asian patients in the adjuvant setting and thus may be considered as a potential new standard of care for resected BTC in the Asian population.

SACT in first line without biomarker guidance
Since 2010 until recently, the pivotal ABC-02 phase III trial set the standard first-line treatment for metastatic BTC (mBTC) with a chemotherapy combination therapy of gemcitabine with cisplatin which was superior to gemcitabine monotherapy in terms of median progression-free survival (mPFS) and mOS [11.7 versus 8.1 months; hazard ratio (HR), 0.64; 95% confidence interval (CI), 0.52-0.80;p < 0.001]. 44Recently, the results of the practice changing TOPAZ-1 phase III trial were published that showed for the first time the clinical efficacy and value of immunochemotherapy consisting of the immune checkpoint inhibitor durvalumab with the previous standard chemotherapy gemcitabine + cisplatin in first-line versus gemcitabine + cisplatin.The immunochemotherapy led to a significantly better mPFS [7.2 versus 5.7 months, HR 0.75 (0.63-0.89)] and mOS [12.8 versus 11.5 months, HR 0.80 (0.66-0.97)] and higher OS rates at 24 months with an improvement of 14.5% (24.9 versus 10.4% estimated OS at 24 months). 45sed on these results, durvalumab was approved by both FDA and EMA for locally advanced or metastatic BTC. 45The efficacy of immunotherapy was confirmed by the phase III KEYNOTE-966 trial (NCT04003636) that tested pembrolizumab in conjunction with gemcitabine and cisplatin against gemcitabine and cisplatin + placebo chemotherapy-naïve BTC patients are 1:1 randomized to receive either. 46,47e German, open-label, 1:1 randomized, phase II NIFE trial (NCT03044587) compared the platinum-free combination nanoliposomal irinotecan (nal-IRI) + 5-fluorouracil (5-FU)/ folinic acid (leucovorin) in arm A versus the standard therapy gemcitabine + cisplatin in arm B for treatment-naïve BTC patients.The NIFE trial met its primary endpoint with a PFS-rate of 51% at 4 months in the ITT population (arm A).Overall response rate (ORR) was 24.5% versus 11.9%. 48e addition of nab-paclitaxel to gemcitabine + cisplatin versus gemcitabine + cisplatin and placebo was tested in the phase III randomized trial SWOG S1815 (NCT03768414) in newly diagnosed advanced BTC, however failed to show a statistically significant improvement in mOS for the triple combination.
The data regarding anti-EGFR strategies for BTC management are contradictory.0][51][52][53] In contrast, two non-randomized phase II trials suggested a potential benefit of anti-EGFR therapies. 54,55garding the use of the combined use of immunotherapy and anti-VEGF therapy, the randomized phase II trial IMbrave 151 tested atezolizumab in conjunction with bevacizumab and chemotherapy against atezolizumab + placebo and chemotherapy in patients with advanced BTC.However, this trial did not meet its primary endpoint of PFS. 56rthermore, there are ongoing biomarkerguided phase III trials that will be discussed in the respective sections of the review.Table 3 gives a short overview of trials of first-line treatment for BTC.

SACT in second line without biomarker guidance
Currently -regardless of the subentity -the standard of care in second line is FOLFOX (combination of folinic acid, 5-FU, and oxaliplatin) after failure of gemcitabine + cisplatin established by the ABC-06 trial, the only phase III trial in second line. 57wever, the application of FOLFOX does not seem always practicable in BTC patients, who did not primarily respond to the platinum-based firstline treatment and who have experienced adverse events, including peripheral polyneuropathy.
Alternative platinum-free treatment options were also tested in second line for BTC.
Two phase II trials tested the efficacy of nal-IRI combined with 5-FU and folinic acid in the interventional arm versus 5-FU and folinic acid in the control arm after failure of gemcitabine + cisplatin: The NIFTY trial was conducted in South Korea and the interventional arm achieved an mPFS of 7.1 versus 1.4 month and an mOS of 8.6 versus 5.5 months. 58In contrast, in the German NALIRICC trial, the interventional arm achieved   59 The recently presented phase II NAPOLI-2 trial is a single-arm trial, which tested nal-IRI combined with 5-FU and folinic acid at oncologic centers in USA.Similarly to the NIFTY trial, this trial observed a therapeutic efficacy of this therapy regime, achieving a mPFS of 3.9 months and a mOS of 9.5 months. 60Thus, the data on the use of nal-IRI are contradictory and more trials are needed in this regard.
The role of immunotherapy in second line was investigated in three phase II trials: CA209-538, LEAP-005, and REGOMUNE.The Australian trial CA209-538 examined the chemotherapyfree combination regimen of ipilimumab and nivolumab and yielded an ORR of 23% (all partial responses), however with a relatively modest mPFS of 2.9 months and mOS of 5.7 months. 61e combination of lenvatinib + pembrolizumab in LEAP-005 yielded an ORR of 10% (all partial responses) and a mPFS of 6.1 months and a mOS of 8.6 months. 62REGOMUNE investigated regorafenib + avelumab that led to promising results, including an ORR of 14% (all partial responses), a mPFS of 2.5 and a mOS of 11.9 months. 635][66][67] The TreeTopp trial failed to significantly improve the mPFS. 68Table 4 gives a short overview of trials for second-line BTC treatment.
Table 4 gives a short overview of ongoing trials.

Targeted treatments in palliative setting
In recent years, efforts have been made to progressively individualize therapy options in specific cancers.Emerging techniques, such as profiling tumor molecular alterations and mutations, identifying molecular targets amenable to specific treatments, and developing drug treatments specific to an individual patient, have created the potential for novel and effective therapies. 69,70he most common mutations in BTC are TP53, KRAS, CDKN2A/B, and SMAD4. 71None of these mutations are currently targetable, except for KRAS G12C that can be targeted off-label with Sotorasib. 72In this work, the genetic aberrations are ranked and rated according to the ESMO ESCAT (ESMO Scale for Clinical Actionability of molecular Targets) to objectify their value as clinical targets based on available strength of evidence. 73,74In a study of 327 BTC patients conducted by Verdaguer et al., 56.3% had actionable molecular aberrations according to ESCAT.Patients who received molecularbased targeted therapy based on their molecular profile had an mOS of 22.6 months, compared to 14.3 months in those without actionable ESCAT alterations. 74Thus, targeted therapies based on the molecular information are crucial for improving the clinical outcome.
Table 5 classifies the various targets based on clinical evidence of utility according to the ESMO ESCAT framework.
IDH1.IDH1 (isocitrate dehydrogenase 1) mutations are found in approximately 10-15%, predominantly in the iCCA, particularly in the variants small duct-iCCA and cholangiolocarcinoma-iCCA. 76,77 IDH1 mutations can be targeted by Ivosidenib, which is an oral IDH1 inhibitor that has been evaluated in the global, randomized, double-blind, placebo-controlled phase III clinical ClarIDHy trial enrolling patients with pretreated IDH1 mutant cholangiocarcinoma.The primary endpoint, namely mPFS, was met with a significant improvement of 1.3 month (2.7 versus 1.4 month; HR 0.37).An mOS showed a trend toward improvement with Ivosidenib, but it was not statistically significant (10.3 versus 7.5 months, HR 0.79).However, when adjusted for crossover, OS was significantly better with Ivosidenib (mOS 5.1 months with placebo versus not reached with Ivosidenib. 78Ivosidenib received an ESMO-MCBS score of 3 out of 5 points. 79osidenib, an oral IDH1 inhibitor, has been studied in a phase III clinical trial (ClarIDHy) for patients with pretreated IDH1 mutant cholangiocarcinoma.The trial demonstrated a significant improvement in mPFS with Ivosidenib compared to placebo (2.7 months versus 1.4 months, HR 0.37).

FGFR. The FGF pathway is composed of 22
FGFs and 4 different transmembrane receptors with intracellular tyrosine kinase domains, FGFR 1-4. 80In this context, gene fusions that involve the FGFR2 are particularly clinically relevant, as     [82][83][84][85][86][87] In all these trials, the mPFS was well above 5 months with an ORR of more than 20%. 88,89Pemigatinib and futibatinib are the only FGFR-inhibitor that have been granted approval from both FDA and EMA and received an ESMO-MCBS score of 3 from 5 points. 90,91All aforementioned inhibitors -except for futibatinib -are reversible inhibitors. 92[95]  BRAF V600E.BRAF is a kinase and part of the RAS-RAF-MEK-ERK pathway, which is a critical signaling cascade in oncogenesis.The most common and the clinically most relevant BRAF mutation is the BRAF V600E point mutation that is detected in 5% in iCCA cases. 96 the phase II, non-randomized ROAR basket trial, Subbiah et al. investigated the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib in 43 pretreated BTC patients, with the majority (91%) having iCCA and harboring the BRAF V600E mutation.The targeted therapy combination resulted in an ORR of 56%, with an mPFS of 6.7 months, and an mOS of 14.5 months. 97,98cently, dabrafenib + trametinib was approved by the FDA as a tissue-agnostic therapy option for BRAF V600E mutant solid tumors, including BTC. 99 HER2.HER2 (also known as ERBB2) amplification is detected in approximately 5% of all BTC cases, particularly in gallbladder carcinoma and in eCCA, where it is found between 15 and 20%. 100,101It is associated with worse OS. 102 Several clinical phase II trials explored anti-HER2targeted therapies in pretreated HER2-positive BTC patients that have shown clinical efficacy, including trastuzumab deruxtecan, trastuzumab + mFOLFOX, trastuzumab + pertuzumab, trastuzumab + tucatinib, and zanidatamab.[105][106][107] In contrast, based on two phase II trials, lapatinib does seem to be very active in BTC. 108,109e phase II basket trial SUMMIT is the only trial that investigated the irreversible pan-HER oral TKI neratinib in BTC patients with HER2 mutations and achieved an ORR of 16% and an mPFS of 2.8 months and an mOS of 5.4 months. 110R, MSI, TMB.Aberrations in genes of the DNA damage response (DDR) are found in over 20% BTC patients, with a higher occurrence frequency in eCCA. 111The presence of an aberrated DDR is a predictive marker for platinum-based therapies. 112These genes include, but are not limited to: BRCA1/2, PALB2, ATM, ATR, RAD51, PTEN, FANCA, FANCAB, MRE11, and ARID1A. 113In a retrospective study, Spizzo et al. investigated 1292 BTC samples and identified BRCA mutations in 3.6% of all cases and noticed that these mutations were associated with a higher rate in subjects with MSI-H (microsatellite instability-high) (19.5 versus 1.7%, p < 0.0001) and tumors with higher tumor mutational burden (TMB), regardless of the MSI status (p < 0.05). 114ue to the concept of synthetic lethality, BRCA deficient tumors are sensitive to therapies with PARP inhibitors. 115Currently, two phase II trials

TherapeuTic advances in
22 journals.sagepub.com/home/tamexplore the clinical efficacy of the PARP inhibitor olaparib in DDR aberrated BTC (see Table 2).
MSI-H is a predictive marker for immunotherapy and is found in below than 5% of BTC patients. 116he multicohort phase II trial KEYNOTE-158 included 22 pretreated BTC patients with MSI-H who were treated with pembrolizumab. 117An ORR of 40.9% was achieved.The mPFS and mOS were 4.2 and 24.3 months, respectively.The mDOR was not reached. 118Based on these results, pembrolizumab received the first tumor tissue-agnostic approval from the FDA for the treatment of MSI-H positive solid tumors in 2017. 119Recently, EMA granted approval to MSI-H positive BTC, who have disease progression on or following at least one prior therapy.
Tumors with a high TMB (TMB-H) tend to genomic instability resulting in an increased likelihood of tumor-specific neoantigens recognizable by the immune system.TMB is commonly defined as the overall number of somatic nonsynonymous mutations per megabase (Mut/Mb).TMB-H is defined as 10 mutations/megabase and has been shown to be more susceptible to immunotherapy than tumors with a low TMB.The frequency of TMB-H is reported at approximately 4% of BTC patients. 120 2020, FDA approved pembrolizumab for patients with TMB-H solid tumors based on the KEYNOTE-158 trial. 121her markers.Gene fusions involving one of the neurotrophic tropomyosin receptor kinases (NTRK1, NTRK2, and NTRK3) can act as an oncogenic driver.These gene fusions are a rare finding in BTC, typically below 1%. 122,123[126][127] Other rare findings occurring in BTC are RET gene fusions that have been investigated and targeted in the two phase I/II basket trials, ARROW and LIBRETTO-001. 128,129In the former trial, pralsetinib was tested in three BTC patients with RET fusions and achieved a clinical response in two patients. 128In the latter trial, selpercatinib was evaluated in 41 patients, including 2 BTC patients, and achieved an ORR of 44% with a mDOR of 24.5 months. 129Based on this trial, FDA granted selpercatinib an approval for locally advanced or metastatic RET fusion-positive solid tumors. 130r other markers such as PIK3CA mutations and MET amplifications the evidence for targeted therapies in BTC is scarce.
KRAS G12C, albeit a rare finding (1%), is amenable to targeted therapy. 131e Table 4 for further details.See Figure 1 for an overview of the current treatments for BTC.

Locoregional treatments in palliative setting
As unresectable iCCA often manifests in the liver, loco-regional treatments have been utilized in such cases.These treatment techniques encompass a range of approaches, from ablation techniques, to external beam radiotherapy (EBRT) to and intra-arterial therapies (IATs).[134] Ablation techniques.Ablation techniques involve minimally invasive procedures aimed at inducing coagulative necrosis within the tumor.Commonly utilized ablation techniques include radiofrequency ablation (RFA), microwave ablation (MWA), and irreversible electroporation (IRE).Ablation procedures have predominantly been studied in patients with tumors that cannot be surgically removed due to cirrhosis or those experiencing tumor recurrence following prior resection.
As reported in a meta-analysis by Edeline et al., ablation was associated with a pooled complete response rate of over 90%, and with a pooled weighted mean OS of over 30 months. 135Based on this meta-analysis, the ESMO recommends considering ablation for patients with intrahepatic cholangiocarcinoma (iCCA) of ⩽3 cm in size who have contraindications to surgery. 75ternal beam radiotherapy.EBRT involves the delivery of high-energy radiation beams from an external source to the tumor site.Data regarding its use are limited and heterogeneous and should be investigated further in prospective clinical trials. 75ntra-arterial therapies.IAT approaches involve the targeted delivery of therapeutic agents directly into the hepatic arterial supply of the tumor.The key IAT modalities TACE, SIRT, and HAI have been mostly studied retrospectively.Two metaanalyses supported the use of TACE in iCCA. 136,137HAI and SIRT combined with systemic chemotherapy were explored in single-arm phase II trials in iCCA and yielded promising results. 138,139Thus, IAT might be considered combined with systemic antitumoral therapy in iCCA limited to the liver in selected cases. 75

Role of cirrhosis in advanced intrahepatic cholangiocarcinoma
Based on the European Network for the Study of Cholangiocarcinoma (ENSCCA) registry over 10% of patients with iCCA have cirrhosis. 140irrhosis has been reported as a risk factor for the development of cholangiocarcinoma. 141In advanced iCCA, it is significantly associated with more grade 3/4 chemotherapy-induced toxicities and shorter OS. 142,143 Thus, early diagnosis, grading and consideration of cirrhosis in therapeutic management, particularly the dose of chemotherapy, is recommended. 142

Discussion
Neoadjuvant treatment can convert unresectable BTC to resectable, enabling curative resection attempts.Although neoadjuvant therapy may be suitable for locally advanced disease, its routine use in upfront resectable CCA is not well established, and its impact on survival outcomes needs further investigation.Several issues, such as the timing of surgical resection after neoadjuvant therapy, duration of treatment, safety during preoperative biliary drainage and embolization, and risks of major hepatic resection, require thorough assessment in prospective studies.Large-scale clinical trials are essential to establish a standardized neoadjuvant therapy regimen for both resectable and unresectable CCA.Thus, the authors suggest that neoadjuvant treatment should not be proposed outside of clinical trials and only with histological proof.
Despite surgical resection with curative intention, the risk of recurrence remains high for BTC.
A combined perioperative therapeutic approach is crucial in reducing the relapse rate.
By optimizing treatment sequences and synergizing modalities, a multimodal treatment strategy -as for example pursued in the phase II SIROCHO trial (NCT05265208) -may aid in reducing the chances of recurrence.
After more than a decade of stagnancy in novel treatment options for advanced and metastatic BTC, the molecular profiling has led to treatment stratification, which is has improved the prognosis of the patients, thereby sparing unnecessary toxicities from chemotherapy.Thus, an increasing number of molecular targets have been described and new targeted agents, such as ivosidenib and pemigatinib and futibatinib, have been developed and successfully tested in prospective clinical phase II and III trials and brought new drugs into standard treatment algorithm.
Ongoing trials are currently testing these and other targeted agents in the first-line setting of advanced and metastatic BTC.
Furthermore, immune checkpoint inhibitors have been investigated in a variety of entities, including BTC.In 2010, the positive phase III ABC-02 trial set a new standard with the systemic chemotherapy combination with gemcitabine + cisplatin, which was for a long time the mainstay of the BTC therapy.However, the phase III TOPAZ-1 trial established the immune checkpoint inhibitor durvalumab combined with chemotherapy as a first-line treatment and underlined the potential for immunotherapy in BTC.
Thus, both immunotherapy and targeted therapies are shaping and enriching the therapeutic armamentarium of BTC management.
However, there is still room for improvement.
For the application of immunotherapy, the identification of new predictive biomarkers -apart from MSI-H and TMB-H -would be crucial to better select and stratify patients that may have a long-term benefit from this therapy type.Another clinical priority is to identify primary and secondary therapeutic resistance mechanisms.Even the use of targeted therapies, such as ivosidenib and pemigatinib, produces an mPFS under 8 months.Thus, to increase the clinical efficacy of therapies, these resistance mechanisms have to be overcome by introducing new potent therapeutics, effective therapy combination, and rational therapy sequence strategies.
Furthermore, the molecular heterogeneity of BTC subentities should be considered in future trials.Multicohort trials covering the different subentities would be one way to increase the accuracy and quality of drug investigation in BTC.
Currently, numerous clinical trials are ongoing, and many more trials are designed that will help to clarify these open questions.

Figure 1 .
Figure 1.Palliative treatment options for advanced/metastatic Biliary Tract Cancer.
et al.

Table 2 .
Overview of ongoing prospective neoadjuvant trials in cholangiocarcinoma.

Table 3 .
Trials of first-line systemic treatment for BTC.

Table 4 .
Trials after at least one prior line of systemic therapy for BTC.

Table 5 .
75assification of the targets in BTC according to the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESMO ESCAT framework) adapted from Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment, and follow-up.75 Table1gives a short overview of trials of first-line treatment for BTC.